Biousian Biosystems Inc. (BBI) intends to develop novel, glycosylated, deltorphin-based peptides as orally available drugs for the treatment of chronic inflammatory pain. By targeting a 4-selective mechanism, it is anticipated that compounds with improved efficacy and fewer side effects, including less abuse liability and addiction potential, will result. Glycosylation of 4-specific compounds will produce additional advantages as many biological functions are mediated by glycans, reflecting the emerging importance of glycoconjugate chemistry in the design of novel drugs. Historically, peptide-based drug candidates have poor stability, short half-lives and limited CNS penetration. However, glycosylation of peptides can overcome these issues, resulting in improved stability, enhanced PK and increased CNS bioavailability. A successful glycopeptide drug would represent a novel, first-in-class therapeutic agent with significant advantages, thereby transforming the development of peptide as well as pain therapeutics. BBI will use a process, termed CarboSyn" to synthetically modify endogenous, biologically-active peptides through glycosylation. We have previously validated CarboSyn" technology on enkephalin-based peptides. An early drug candidate was identified that targeted both the 4 and 5 opioid receptors (DOR and MOR, respectively) and had improved properties over the parent peptide. This success encouraged us to apply the technology to a DOR-selective scaffold, deltorphin. Based upon our and other's research, DOR-selective compounds offer significant advantages in analgesic activity with the potential for fewer side effects than compounds with a significant MOR-preferring component. Preclinical data demonstrate increased efficacy with better safety/tolerability profiles for DOR agonists relative to morphine and other MOR agonists. In this proposal, we will apply glycosylation technology to the deltorphin family of DOR-preferring peptides, further enhancing the potential therapeutic benefits that this target offers. The focus of this work is to discover a novel DOR-selective early drug candidate that will be developed for the treatment of chronic inflammatory pain. We intend to synthesize 15-20 novel glycopeptides from the deltorphin scaffold (Specific Aim 1) and screen the compounds for in vitro binding, selectivity and activity at opioid receptors (Specific Aim 2). High affinity (Ki<10nM), DOR-selective (100-fold) compounds will be tested in vivo (Specific Aim 3) in an acute pain model and 1-2 compound(s) will be tested in a sub-acute inflammatory pain model, both of which are sensitive to DOR agonists. We will generate additional intellectual property for BBI and identify an early developmental drug candidate from this work that subsequently will be advanced into an orally available lead drug candidate for the treatment of chronic inflammatory pain. Upon completion of this Phase I SBIR, additional funding will be requested (Phase II SBIR and private investment) for lead optimization, oral formulation, PK and other IND-enabling studies with the ultimate goal of an IND submission, a Phase I study and development of a strategy to partner and commercialize the drug candidate. PUBLIC HEALTH RELEVANCE: Although opioid analgesics such as morphine remain the standard of care for moderate to severe, acute and chronic pain, they are plagued with issues of tolerance and adverse effects such as bowel dysfunction, respiratory depression and addiction. Biousian Biosystems Inc (BBI) is developing novel glycosylated peptide-based, 4 opioid receptor-targeted drugs to treat chronic pain with improved efficacy and without the significant side effects of currently used opioid analgesics. BBI will generate novel, glycosylated peptides that overcome the challenges associated with developing peptide therapeutics and will provide an important contribution to pain management.